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Cytogenetics and Molecular Genetics

Prognostic implications and molecular associations of NADH dehydrogenase subunit 4 (ND4) mutations in acute myeloid leukemia

Leukemia volume 26, pages 289–295 (2012)Cite this article

Abstract

To study the prevalence and prognostic importance of mutations in NADH dehydrogenase subunit 4 (ND4), a mitochondrial encoded transmembrane component of the electron transport chain respiratory Complex I, 452 AML patients were examined for ND4 mutations by direct sequencing. The prognostic impact of ND4 mutations was evaluated in the context of other clinical prognostic markers and genetic risk factors. In all, 29 of 452 patients (6.4%) had either somatic (n=12) or germline (n=17) ND4 mutations predicted to affect translation. Somatic mutations were more likely to be heteroplasmic (P<0.001), to occur in predicted transmembrane domains (P<0.001) and were predicted to have damaging effects upon translation (P<0.001). Patients with somatically acquired ND4 mutations had significantly longer relapse-free survival (P=0.017) and overall survival (OS) (P=0.021) than ND4wildtype patients. Multivariate analysis also demonstrated a tendency for increased survival in patients with somatic ND4 mutations (RFS: hazard ratio (HR) 0.25, confidence interval (CI) 0.06–1.01, P=0.052; OS: HR 0.29, CI 0.74–1.20, P=0.089). Somatic ND4mutated patients had a higher prevalence of concomitant DNMT3A mutations (P=0.023) and a higher percentage of the NPM1/FLT3-ITD low-risk genotype (P=0.021). Germline affected cases showed higher BAALC (P=0.036) and MLL5 (P=0.051) expression levels. Further studies are warranted to validate the favorable prognostic influence of acquired ND4 mutations in AML.

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Acknowledgements

We thank all patients and physicians for provision of study material; Kerstin Görlich, Elvira Lux, Sylvia Horter, Diana Dudacy, Irina Schäfer, Susanne Wolf and Uwe Borchert for their support in sample and data acquisition; Dr Sarvari Velaga for helping in the preparation of Figure 2; Dr Thomas Winkler and Dr Olivier Bernard for critically reading the manuscript. We acknowledge the assistance of the Cell-Sorting-Core-Facility of the Hannover Medical School supported in part by Braukmann-Wittenberg-Herz-Stiftung and Deutsche Forschungsgemeinschaft. This study was supported by the Hannelore-Munke Fellowship, grants HILF 2010 and no. 109686 by the Deutsche Krebshilfe awarded to FD; grant no. M 47.1 from the HW & J Hector Stiftung; and grants no. 01GI0378 (Kompetenznetz ‘Akute und chronische Leukämien’) and 01KG0605 from the Bundesministerium für Bildung und Forschung.

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Authors and Affiliations

  1. Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany

    F Damm, T Bunke, F Thol, B Markus, K Wagner, G Heil, C W M Reuter, K Püllmann, M Heuser, J Krauter, A Ganser & M A Morgan

  2. Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany

    G Göhring & B Schlegelberger

  3. Department of Internal Medicine V, Klinikum L,

    G Heil

  4. ü,

    G Heil

  5. denscheid, L, ü, denscheid, Germany

    G Heil

  6. Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany

    R F Schlenk, K Döhner & H Döhner

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Damm, F., Bunke, T., Thol, F. et al. Prognostic implications and molecular associations of NADH dehydrogenase subunit 4 (ND4) mutations in acute myeloid leukemia. Leukemia 26, 289–295 (2012). https://doi.org/10.1038/leu.2011.200

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